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6211 Marsico Hall


Mycobacterial biology, pathogenesis, and therapeutic development

Mycobacterium tuberculosis, the bacterial pathogen that causes tuberculosis, remains a serious world health problem. In 2019, there were 10 million new cases and 1.4 million deaths (4,000 deaths each day) from tuberculosis. My laboratory studies the basic mechanisms used by M. tuberculosis to cause disease, and we are actively collaborating on the development of new therapeutic strategies to treat tuberculosis. We additionally study nontuberculous mycobacteria (NTM), which are increasingly prevalent pathogens associated with chronic pulmonary infections in people living with lung diseases, such as cystic fibrosis and chronic obstructive pulmonary disease.

Basic Biology and Pathogenesis of M. tuberculosis. A major focus of our research is to identify the protein secretion systems of M. tuberculosis and the roles that M. tuberculosis secreted proteins play in pathogenesis, particularly in enabling M. tuberculosis to survive within macrophages. We study a specialized secretion system, called the SecA2 system. The SecA2 system secretes the SapM phosphatase, which has a role in promoting M. tuberculosis survival in macrophages. SapM prevents M. tuberculosis from being delivered to degradative phagolysosomal compartments in the macrophage. Most recently we discovered a chaperone protein named SatS that protects SapM from degradation and assists in SapM secretion out of the bacteria. Our mechanistic studies are defining the pathway that SapM takes to be delivered into the macrophage environment in order to protect M. tuberculosis from destruction by macrophages. We are also studying M. tuberculosis transporter systems (Mce transporters) that import lipids and are required for pathogenesis. The knowledge gained from our studies has the potential to reveal new targets for tuberculosis drugs and to drive development of new treatment strategies for tuberculosis.

Therapeutic development for tuberculosis. To address the growing problem of drug resistant M. tuberculosis (~500,000 new cases in 2019), new tuberculosis drugs with novel modes of action are needed. Through on-going collaborations, we are testing new and repurposed compounds for their ability to inhibit M. tuberculosis during in vitro growth and during growth in macrophages. In collaboration with Dr. Anthony Hickey (UNC, RTI), we are also investigating inhaled therapies to treat tuberculosis. One of the drugs being evaluated is inhaled pyrazinoic acid. Pyrazinoic acid is the active moiety of the prodrug pyrazinamide (PZA). PZA is a critical component of front-line therapy for drug sensitive tuberculosis, and it is included in treatment regimens for multidrug resistant tuberculosis. However, the rise in PZA resistant M. tuberculosis jeopardizes future use of PZA. Because pyrazinoic acid is active on the largest category of PZA resistant M. tuberculosis strains, pyrazinoic acid treatment has the potential to replace PZA for treating drug resistant strains. However, when orally delivered pyrazinoic acid is ineffective in treating tuberculosis. Thus, we are evaluating the efficacy of treating tuberculosis with pyrazinoic acid that is directly delivered via inhalation to the primary site of M. tuberculosis infection in the lung.

Therapeutic development for Nontuberculous mycobacteria (NTM). Mycobacterium abscessus is one of the most common NTMs encountered in pulmonary NTM disease and it is the most difficult to treat. M. abscessus is multidrug resistant and there is no systematically proven regimen that is effective and tolerable. To address the need for therapies to treat drug resistant M. abscessus, we are testing compounds for their ability to inhibit M. abscessus. We are also exploring the potential of using bacteriophages to treat M. abscessus disease. Bacteriophages (phages) are viruses that infect and kill bacteria. Because M. abscessus grows in macrophages and in biofilms we are investigating the ability of phages to kill M. abscessus in these environments.

Select References:

Rank, L., Herring, L.E. and Braunstein, M. (2021). Evidence for the mycobacterial Mce4 transporter being a multiprotein complex. J. Bacteriol. 201:e00685-20.

Bird, K.E., Xander, C., Murcia, S., Schmalstig, A.A., Emanuele, M.J., Braunstein, M. and Bowers, A.A. (2020). Thiopeptides induce proteasome-independent activation of cellular mitophagy. ACS Chem Biol. 15:2164-2174.

Miller, B.K., Hughes, R., Ligon, L.S., Rigel, N.W., Malik, S., Anjuwon-Foster, B.R., Sacchettini, J.C. and Braunstein, M. (2019). SatS is a chaperone for the SecA2 export pathway of Mycobacterium tuberculosis. eLIFE. 8:e40063.

Braunstein, M., Hickey, A.J. and Ekins, S. (2019). Why wait? The case for treating tuberculosis with inhaled drugs. Pharmaceutical Research. 36:166.

Braunstein, M., Bensing, B.A. and Sullam, P.M. (2019) The two distinct types of SecA2-dependent export systems. In Protein Secretion in Bacteria. Eds. Christie, P., Cascales, E. and Sandkvist, M. (American Society for Microbiology Press). p.29-42.

Zulauf KE, Sullivan JT, and Braunstein M. (2018). The SecA2 pathway of Mycobacterium tuberculosis exports effectors that work in concert to arrest phagosome and autophagosome maturation. PLOS Pathogens. 14(4):e1007011.

Montgomery, S.A., Young, E.F., Durham, P.G., Zulauf, K.E., Rank, L., Miller, B.K., Hayden, J.D., Welch, J.T., Hickey, A.J. and Braunstein, M. (2018). Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis. PLOS ONE 13(9):e0204495.

Perkowski, E.F., Zulauf, K.E., Weerakoon, D., Hayden, J.D., Ioerger, T.R., Oreper, D., Gomez, S.M., Sacchettini, J.C., and Braunstein, M. (2017). The EXIT Strategy: An approach for identifying bacterial proteins exported during host infection. mBio. 8(2): e00333-17.

Perkowski EF, Miller BK, McCann JR, Sullivan JT, Malik S, Allen IC, Godfrey V, Hayden JD, Braunstein M. (2016). An orphaned Mce-associated membrane protein of Mycobacterium tuberculosis is a virulence factor that stabilizes Mce transporters. Mol. Microbiology. 100:90-107.

Link to My Bibliography